Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology. It is characterized by synovial inflammation with frequent progression to articular cartilage and bone destruction. The synovial inflammatory response in RA consists predominately of T lymphocytes, mostly T helper cells (Th), with fewer numbers of macrophages and B lymphocytes. The Th cells can be divided into two overlapping subpopulations of important functional significance, Th1 and Th2 cells. Th1 cells secrete IL-2 and interferon- and regulate cell-mediated responses. Th2 cells secrete IL-4, IL-5, and IL-10, and mediate humoral responses. Most of Th cells in the rheumatoid joint appear to belong to the Th1 subpopulation. The synovial tissue in RA exhibits other features typical of a cell-mediated response, including hypervascularity, upregulation of cell adhesion molecules, and overexpression of pro-inflammatory cytokines such as IL-1 and tumor necrosis factor (TNF)- . IL-4, a cytokine produced by Th2 cells and macrophages, has primarily immunosuppressive and anti-inflammatory properties. The inhibitory effects of IL-4 have been observed in animal models of arthritis where it can ameliorate joint inflammation. The purpose of the present study is to determine the safety and tolerability and potential clinical efficacy of subcutaneous doses of recombinant human IL-4 (rHuIL-4) in patients with RA. The study is a multicenter, double-blind, placebo- controlled, escalating dose (0.5, 1.0, and 2.0 5g/kg) clinical trial with a dosing period of 6 weeks. The main outcomes for the study are the frequency and severity of adverse effects and the American College of Rheumatology Core Disease Measures. Study activity during the specified time period consists of the screening evaluation of a single patient. SIGNIFICANCE OF THE STUDY: RA is widely believed to be a Th1-mediated disease, although the data to support this hypothesis is circumstantial. For example, Th1 cells are associated with cellular immune responses, which seems to fit with the characteristics of rheumatoid joint inflammation, and T cell clones isolated from synovial tissue of RA patients most often secrete Th1 cytokines. Additional insights into whether RA is a Th-driven response in RA may be obtained by examining the treatment and biological effects of cytokines which downregulate Th1 responses.